This application outlines a multidisciplinary research program at the cross-section of anticancer drug development, molecular and structural biology, and biocoordination chemistry. The proposed research was sparked by the recent discovery of the unusual DNA damage profile of a cytotoxic platinum-acridine hybrid agent (PT-ACRAMTU). Unlike the clinical cisplatin-based agents, this drug does not cross-link DNA bases but induces structurally unique coordinative-intercalative monoadducts in both the DNA major and minor grooves. In particular, the formation of adducts with adenine-N3 in the minor groove is a damage mechanism previously unknown in platinum antitumor chemistry. Novel types of DNA lesions, such as PT-ACRAMTU's monoadducts, have the potential to overcome tumor resistance by providing alternate pathways to cell death and therefore should be pursued rigorously at the preclinical development stage. PT-ACRAMTU-type conjugates have demonstrated enhanced cytotoxic activity compared with cisplatin in various solid tumors, especially non-small cell lung cancers (NSCLC), which are difficult to treat with current regimens. Spanning the range from basic science to biomedical application, the proposed experiments aim to unravel the agent's unusual DNA-binding mechanism and elucidate the DNA structural impact caused by its adducts. The results expected from these studies will be used to develop the prototypical agent, which has already demonstrated potent activity in xenograft models, into a clinically useful therapy that acts through a mechanism unlike that of clinical platinum drugs. Specifically, the research will (1) use modular synthesis to produce PT-ACRAMTU derivatives with enhanced target selectivity and minimal side effects, (2) study their DNA-damage profiles using newly developed (bio)chemical assays, (3) test the hypothesis that PT-ACRAMTU-type adducts are able to evade nucleotide excision repair (NER) because they do not bend or destabilize DNA, and (4) establish relationships between chemical properties, the specific type of lesion formed within nuclear DNA, its persistence in NER-proficient cells, and its cytotoxic and antitumor potential. Thus, the study holds considerable promise of providing novel chemotypes that show activity in tumors inherently insensitive to platinum and chemotherapeutic intervention in general and salvage therapies for cancers that have acquired resistance to cisplatin and other DNA-targeted drugs. PUBLIC HEALTH RELEVANCE: The research described in this proposal is centered on the development of a new platinum-based cancer treatment for chemoresistant using a unique chemical approach. The study has the potential to identify a new class of anticancer drugs for the management of intractable tumors, especially non-small cell lung carcinomas (NSCLC), based on a unique mechanism of action at the cancer cell's DNA previously unknown for platinum containing chemotherapies currently used in the clinic.